PB1980: ASC4KIDS: A MULTICENTER, OPEN-LABEL, PHASE 1B/2 STUDY TO DETERMINE THE DOSE AND SAFETY OF ASCIMINIB IN PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE
Authors: Nobuko Hijiya, Shruti Kapoor, Matthias Hoch, Laurence Descamps, Kohinoor Dasgupta, Ana Paula Torres Cardoso
Journal: HemaSphere (2023)

Topic: 8. Chronic myeloid leukemia - Clinical Background: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the USFDA with subsequent approvals worldwide for patients ≥18 years with Philadelphia chromosome–positive (Ph+) CML-CP treated with ≥2 prior TKIs. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). Aims: This study aims to characterize the pharmacokinetics (PK) and long-term safety profile of asciminib in pediatric patients and identify a pediatric formulation dose leading to asciminib exposure comparable to 40 mg bid in adult patients. Methods: This multicenter, open-label study (NCT04925479) includes patients aged 1 to <18 years with Ph+ CML-CP, without the T315I mutation, treated with ≥1 prior TKIs. In the pediatric formulation group, at least 15 patients will be included in each of the age groups: 1 to <12 years and 12 to <18 years. The study started with an exploratory group of adolescent patients (aged 14 to <18 years; ≥40 kg) treated with the adult dose (40 mg tablet bid) under fasting conditions. The endpoints include a primary endpoint PK, hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulation. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (mini-tablet 1.3 mg/kg with food) to assess the safety and if the exposure in pediatric patients is comparable to that with the adult formulation over the first 28 days. After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort qd regimen): in total, 10 patients (5 per each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for combined bid and qd will be assessed after all patients complete 52 weeks of treatment (total treatment period, 5 years [Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of study. There are 34 study sites in 14 countries worldwide. Results: The exploratory and the pediatric formulation groups recruited 4 patients and 6 patients, respectively, as of February 16, 2023 with a total of 10 patients in the study. Summary/Conclusion: This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric population. This study is sponsored by Novartis. Figure:Keywords: Tyrosine kinase inhibitor, Pharmacokinetic, Pediatric, Chronic myeloid leukemia